Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary carcinoma (OPC), a contagious lung cancer of sheep. JSRV-induced OPC consists of transformed secretary epithelial cells of the lungs: type II pneumocytes and Clara cells. A characteristic feature of OPC tumors is the production of large amounts of fluid secreted from the tumor cells containing infectious virus. OPC closely resembles human brochioloalveolar carcinoma (BAC), an adenocarcinoma not associated with cigarette smoking and whole etiology is currently unknown. Thus, OPC is an important model for understanding human BAC pathogenesis.
The JSRV envelope (Env) is a type-I transmembrane protein that has approximately 620 amino acids. The mature full-length Env is composed of a surface domain (SU) and transmembrane (TM) domain linked by disulfide bonds. The JSRV Env protein serves a function of binding virions to the cell surface viral receptor, and also functions as an oncogene. Miller et al. reported that expression of the JSRV Env protein alone in the lungs of mice by using a replication-incompetent adeno-associated virus vector resulted in tumors with a bronchiolo-alveolar localization like those seen in sheep. According to Woottn et al., the tumors were lethal to immunodeficient mice, however, tumor development was almost entirely blocked in immunocompetent mice (Wootton et al. (2005) “Sheep retrovirus structural protein induces lung tumours” Nature 434: 904-907). Wootton et al. did not establish any transgenic mouse carrying JSRV Env in germ line cells.
Dakessian et al. microinjected a DNA construct containing surfactant protein C (SPC) promoter driven JSRV Env (SPC-Env) into fertilized eggs and implanted the eggs into pseudopregnant foster mother (Dakessian et al., (2007) “Tumors in mice transgenic for the envelope protein of Jaagsiekte sheep retrovirus.” Virus Genes 35(1):73-80). They were not able to obtain transgenic mice from the SPC-Env DNA construct and thus concluded that the transgene SPC-Env was lethal to embryos. They switched to a transgene expressing an epitope-tagged JSRV Env under the control of the lung-specific surfactant protein A (SPA) promoter and were able to generate transgenic F1 mice containing SPA-Env-HA transgene showing low efficiency but specific expression in the lung. According to Dakessian et al., only one out of 22 founders gave rise to transgenic F1 progeny that developed tumors in the lung but that founder itself did not develop any tumors. Their transgenic mice had limitations in developing experimental animal model due to the difficulties in maintenance and breeding.
Therefore, a previously unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies, especially in connection with development of an animal model for lung carcinoma.